Microbial pathogens have an extraordinary capacity to develop resistance to antimicrobial agents.[1] Methicillin-resistant Staphylococcus aureus (MRSA) is a prominent nosocomial pathogen causing community-acquired pneumonia (CAP) and complicated skin and soft tissue infections (SSTIs). Cephalosporins are a class of Beta-lactam antibiotics with a broad spectrum of activity, proven efficacy and favourable safety profile, making it one of the most commonly prescribed classes of antimicrobials.[2] However, all the four generations are inactive against MRSA. Ceftaroline Fosamil, a fifth-generation Cephalosporin,[3] was synthesised by Takeda Pharmaceutical Co., Ltd and developed by Cerexa, Inc. and Forest Laboratories, Inc.,[2],[4] and it gained the FDA approval in 2010. The Clinical and Laboratory Standards Institute, however, has considered it under a new subclass 'Cephalosporins with anti-methicillin-resistant Staphylococcus aureus activity'.[2],[5] The 1, 3 thiazole ring attached to three-position of Cephalosporin nucleus and Oxime group in C7 Acyl moiety confers enhanced activity against MRSA.[2]

It is a water-soluble prodrug, rapidly dephosphorylated to the active form, Ceftaroline, in plasma. Less than 20% of the drug is plasma protein bound. Elimination half-life is about 2.7 h, the maximum observed concentration is 21 μg/mL and the area under the concentration-time curve is 56 μg h/mL, with no appreciable accumulation. It is excreted through kidneys and dosage adjustment is recommended for patients with creatinine clearance ≤50 mL/min. Not metabolised by cytochrome P450 enzymes, so less propensity for drug-drug interactions. It exhibits time-dependent killing. The amount of time the serum concentration remains above the minimum inhibitory concentration represents the main pharmacodynamic predictor of efficacy.[6]

Preparations, Dosage and Uses

It is available as 400 and 600 mg single-use vials of sterile powder. The reconstituted solution should be used within 6 h if stored at room temperature or within 24 h if refrigerated.[2] It is used in community-acquired bacterial pneumonia (600 mg intravenous [IV] over 1 h every 12 h for 5-7 days) and acute bacterial skin and skin structure infections including those caused by MRSA (600 mg IV over 1 h every 12 h for 5-14 days).[6]

Adverse Effects

Diarrhoea, nausea, headache, rash and pruritus are the adverse effects. Data are incomplete regarding use in children and are considered as a category B drug in pregnancy.[1],[2]

Clinical Trials

CANVAS I and II trials (randomised, double-blind, multinational Phase III trials) evaluated the efficacy of Ceftaroline for the treatment of SSTIs among 1378 subjects comparing Ceftaroline to Vancomycin ± Aztreonam in 2007. It was found that for treating SSTI, Ceftaroline (600 mg IV every 12 h) was non-inferior to Vancomycin (1 g IV every 12 h) plus Aztreonam (1 g IV every 8 h) administered for 5-14 days. In FOCUS I and II trials (randomised, double-blind, multicentric Phase III trials), 1228 hospitalised adults with moderate to severe CAP were randomised to Ceftaroline (600 mg IV every 12 h) or Ceftriaxone (1 g IV daily) for 5-7 days. The overall clinical and microbiological response rates were similar, demonstrating Ceftaroline to be efficacious, well tolerated and comparable in efficacy and adverse effects to Ceftriaxone in the treatment of CAP.[1]

Conclusion

Ceftaroline Fosamil, a new, broad spectrum Cephalosporin, is a promising approach towards combating MRSA-mediated infections and has been approved for use in CAP and complicated SSTIs.